The present invention relates generally to optical sensors for measuring the pH of a fluid, and more particularly relates to a novel optical sensor system containing a membrane of a fluorescent cellulose acrylamide/acrylamide copolymer. The invention additionally relates to novel fluorescent polymer compositions and membranes made therefrom that may be used in the manufacture of optical sensors. One important application of the invention involves the accurate and precise measurement of pH in the physiological range in blood.
Chemical sensors are generally known for use in a wide variety of areas such as medicine, scientific research, industrial applications and the like. Fiber optic and electrochemical approaches are generally known for use in situations where it is desired to detect and/or measure the concentration of a parameter at a remote location without requiring electrical communication with the remote location. Structures, properties, functions and operational details of fiber optic chemical sensors can be found in U.S. Pat. No. 4,577,109 to Hirschfeld, U.S. Pat. No. 4,785,814 to Kane, and U.S. Pat. No. 4,842,783 to Blaylock, as well as Seitz, xe2x80x9cChemical Sensors Based on Fiber Optics,xe2x80x9d Analytical Chemistry, Vol. 56, No. 1, January 1984, each of which is incorporated by reference herein.
Publications such as these generally illustrate that it is known to incorporate a chemical sensor into a fiber optic waveguide, an electrochemical gas sensor or the like, in a manner such that the chemical sensor will interact with the analyte. This interaction results in a change in optical properties, which change is probed and detected through the fiber optic waveguide or the like. These optical properties of chemical sensor compositions typically involve changes in colors or in color intensities. In these types of systems, it is possible to detect particularly minute changes in the parameter or parameters being monitored in order to thereby provide especially sensitive remote monitoring capabilities. Chemical sensor compositions that are incorporated at the distal end of fiber optic sensors are often configured as membranes that are secured at the distal tip end of the waveguide device or optrode.
Sensors of this general type are useful in monitoring the pH of a fluid, measuring gas concentrations such as oxygen and carbon dioxide, and the like. Ion concentrations can also be detected, such as potassium, sodium, calcium and metal ions.
A typical fiber optic pH sensor positions the sensor material at a generally distal location with the assistance of various different support means. Support means must be such as to permit interaction between the pH indicator and the substance being subjected to monitoring, measurement and/or detection. With certain arrangements, it is desirable to incorporate membrane components into these types of devices. Such membrane components must possess certain properties in order to be particularly advantageous. Many membrane materials have some advantageous properties but also have shortcomings. Generally speaking, the materials must be biocompatible, hemocompatible for use in the bloodstream and selectively permeable to hydrogen ions.
It is also desirable to have these membrane materials be photocurable (such that curing is easier, can be done more rapidly, on a smaller scale, and directly on the optical fiber) and resistant to shear forces (e.g., as present in a bloodstream. It is also preferred, clearly, that a signal of sufficient intensity be produced, such that measurement is as accurate as is reasonably possible. It is additionally desired that the materials used for the sensor membrane be constructed such that pH values in a physiologic blood range may be accurately measured, and that the response time for measuring pH values is relatively rapid. An additional desirable property of a sensor for monitoring pH in blood or other physiologic fluid is that the sensor has minimal sensitivity to interfering substances. The optical pH sensors that are currently available are frequently inadequate with regard to one or more of the aforementioned criteria.
The present invention is addressed to a novel fluorescent polymer composition that is particularly suitable for use as a membrane and a membrane-like component in an optical pH sensor and which provides for optical sensors which meet each of the above-mentioned criteria. That is, optical sensors as provided herein provide for good signal intensity, are rapidly cured with light, and are resistant to shear forces such as those present in flowing blood. In addition, pH sensors prepared using the novel polymer compositions have enhanced barrier properties such that the sensor is minimally sensitive to contaminating substances.
The following references relate to one or more aspects of the present invention:
U.S. Pat. No. 4,785,814 to Kane describes an optical probe useful for measuring pH and oxygen and blood. The device includes a membrane constructed of a hydrophilic porous material containing a pH-sensitive dye.
U.S. Pat. No. 4,842,783 to Blaylock describes a fiber optic chemical sensor which, at the distal end of the optical fiber, is provided with a photocrosslinked polymeric gel having a dye adsorbed therein.
U.S. Pat. Nos. 4,919,891 and 5,075,127 to Yafuso et al. describe a fiber optic sensor in which an indicator composition is encased in a cellulosic overcoat stated to protect and enhance the signal obtained.
U.S. Pat. No. 5,354,825 to Klainer et al., describes a fiber optic sensing device for measuring a chemical or physiological parameter of a body fluid or tissue, in which a polymer containing photoactive moieties is directly bound to the fiber optic tip.
PCT Publication No. WO 90/00572, inventors Boesterling et al., describe the use of a urethane or an acrylamide hydrogel for measuring pH and/or pCO2 in a fluid. The hydrogels are prepared by reacting an isocyanate prepolymer with a derivatized azo dye, i.e., an absorbance dye which is a molecule containing either an amino or hydroxyl functionality.
European Patent Application Publ. No. 0 263 693 describes an optical fiber pH sensor comprising a dye-containing cellulose matrix on the optical surface of the fiber and a carbon-black impregnated overcoating applied over the matrix.
H. J. Hageman et al., xe2x80x9cPhotoinitiators and Photocatalysts for Various Polymerisation and Crosslinking Processes,xe2x80x9din Radiation Curing of Polymers II, ed. D. R. Randell (The Royal Society of Chemistry, 1991), at pp. 46-53, identify a number of materials which will act to catalyze radiation curing of multifunctional monomers or oligomers.
Accordingly, it is a primary object of the invention to address the above-mentioned needs in the art, by providing an optical sensor for measuring the pH of a fluid, which sensor gives rise to the numerous advantages identified above.
It is another object of the invention to address these needs by providing a fluorescent polymer composition for incorporation into such an optical sensor, wherein the fluorescent polymer composition comprises copolymer of a cellulose acrylamide, acrylamide and a polymerizable monomeric fluorescent indicator.
It is still another object of the invention to provide a membrane fabricated from cellulose acrylamide and, optionally, from a copolymer of cellulose acrylamide, acrylamide and/or a polymerizable monomeric fluorescent indicator.
It is yet another object of the invention to provide novel optical sensors comprising a pH sensor means comprising the flourescent polymer composition.
It is a further object of the invention to provide a method for making an optical sensor containing the aforementioned fluorescent composition by polymerizing the composition on the fiber optic tip.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect, then, a fluorescent polymer composition is provided which is useful in an optical sensor for the measurement of pH in a fluid sample. The fluorescent polymer composition comprises a copolymer of (a) cellulose acrylamide, (b) acrylamide, and (c) a polymerizable monomeric fluorescent indicator species. The ratio of the cellulose acrylamide to acrylamide and the ratio of cellulose acrylamide/acrylamide to the fluorescent species is determined to provide the composition with a predetermined apparent pKa. Generally, it is preferred that the ratio be such that the apparent pKa of the composition is in the range of about 6.6 to 8.0, more preferably in the range of about 7.2 to 7.8, most preferably in the range of about 7.2 to 7.4, which in turn optimizes the composition for use in measuring pH in the physiological range. The copolymer has the structure: 
wherein:
is the fluorescent indicator species;
CELLULOSE has the structure 
wherein
each R is independently selected from the group consisting of H, C1 to C6 alkyl, C1 to C6 alkenyl, C1 to C6, alkynyl, and C1 to C6 esters, and R1 is the acrylamide linkage to the copolymer backbone, xe2x80x94OR or CH2xe2x95x90CHxe2x80x94(CO)xe2x80x94NHxe2x80x94;
n is in the range of about 2 to about 500;
x is in the range of about 1 to 30,000;
y is in the range of about 1,000 to 50,000,000;
z is in the range of about 1 to 1,000,000.
In another aspect, a selectively H+-permeable membrane is provided which is useful for fabricating an optical pH sensor. The membrane comprises a copolymeric matrix of the novel fluorescent composition.
In still another aspect, an optical sensor is provided for the measurement of pH in a fluid sample, comprising an optical waveguide to receive light from a light source, and a pH-sensitive medium disposed on the waveguide which fluoresces in response to light from the light source, wherein the intensity of fluorescence is dependent on the pH of the environment being monitored, and the pH-sensitive medium comprises the aforementioned fluorescent polymer composition.
In a further aspect of the invention, an optical sensor is provided as described above further comprising a membrane of cured cellulose acrylamide/acrylamide copolymer applied as an overcoat to the fluorescent polymer composition.
In still a further object of the invention, a method for making an optical sensor for measuring the pH of a fluid is provided. The method comprises providing an optical waveguide having a distal end portion for contacting the fluid, and a proximal end portion for communication with means for receiving a signal from said distal end portion, coating said distal end portion with a solution containing the aforementioned fluorescent polymeric composition, and effecting polymerization of the solution to form a pH sensor means.
In yet a further aspect of the invention, a method for making a fiber optic sensor is provided which involves sequentially providing two or more layers of material at the tip of an optical fiber. The innermost layer is an adhesive layer which adheres to the exposed fiber surface and to a cladding material, if present. The adhesive layer may contain some sort of dye or indicator material, preferably a substantially analyte-insensitive reference dye, and comprises a polymeric material which is partially or fully cured prior to application of additional layers. Overlaying this adhesive layer is a further layer, containing analyte-sensitive materials, also sometimes termed herein the xe2x80x9csensing chemistry.xe2x80x9dAdditional layers may in some cases be present; whether or not such layers are included will depend on a number of factors, e.g., on the end use of the sensor, the materials involved in the xe2x80x9csensing chemistry,xe2x80x9d and the like. The configuration of the inner adhesive layer controls the geometry of the sensing layer applied thereto, and can be manipulated to obtain optimum sensor signal strengths and adhesion. It allows sensors to be manufactured in which there is excellent mechanical adhesion and, optionally, covalent bonding, between the adhesive and sensing layers. The mechanical adhesion results from the deposition of the sensing layer directly on the inner adhesive material, the geometry of the sensing and adhesive layers, and the materials selected for these layers.